Signal transduction mechanisms are menas by which cells relay information from the cellular exterior to the cellular interior. The definition of these various mechanisms is important in understanding cellular proliferation, tumor promotion and neoplastic development. A major signal transduction mechanism recently brought to view is that of phosphatidylinositol turnover with the production of the protein kinase C activating diacylglycerol and the Ca2+ mobilizing inositol-1,4,5- trisphosphate. The present research further defines this signal transduction mechanism and focuses on its role in protein phosphorylation, protein dephosphorylation, Ca2+ release, cell proliferation and tumor promotion. We have identified a protein phosphatase whose activity is stimulated by inositol-1,4,5-trisphosphate. As well, we have identified a phosphoprotein substrate, p37, of protein kinase C that depends on extracellular Ca2+ for translocaiton from the soluble to particulate fraction on stimulation by TPA or serum and have identified p37 as lipocortin. Our short-term goals are to: 1) characterized the inositol-1,4,5-trisphosphate stimulated protein phosphatase; 2) make antibodies to the phosphatase; 3) determine if the phosphatase plays a role in Ca2+ release, Ca2+-dependent cell cycle progression, and tumor promoter action; 4) clone the gene of the protein phosphatase and determine its amino acid sequence; and 5) determine if specific substrates of the inositol- 1,4,5-trisphosphate protein phosphatase and of protein kinase A and C are correlated with Ca2+-dependent cell cycle transitions. It is through a basic understanding of the cell biology and biochemistry of cell proliferation that will allow us to rationally design methods to prevent, interrupt and treat neoplastic disease.